GPR40激动剂SZZ15-11对自发性2型糖尿病KKAy小鼠糖脂代谢紊乱的调控作用

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中文摘要：G蛋白偶联受体40(G protein-coupled receptor 40，GPR40)是G蛋白偶联受体家族成员，对糖脂代谢有重要调控作用。本研究旨在考察新型GPR40激动剂SZZ15-11对自发性2型糖尿病KKAy小鼠糖脂代谢的影响，并探讨其潜在机制。将KKAy小鼠随机分为4组，一组以0。5％羧甲基纤维素钠(sodium carboxymethylcellulose，CMC)灌胃为模型组(vehicle)、一组以TAK875(50 mg·kg-1)灌胃为阳性对照组(TAK)，另两组分别以不同剂量SZZ15-11(50和100 mg·kg-1)灌胃为给药组(SZZ 50 mg·kg-1和SZZ 100 mg·kg-1)，每天一次，共45天。于给药期间，检测空腹血糖、随机血糖、血甘油三酯(triglyceride，TG)和总胆固醇(total cholesterol，TC)水平，进行口服葡萄糖耐量试验和胰岛素耐量试验，同时通过酶联免疫吸附方法(enzyme-linked immunosorbent assay，ELISA)测定小鼠血胰岛素和胰高血糖素水平。实验结束后处死小鼠，取肝组织，测定TG和TC含量，用苏木素-伊红(hematoxylin-eosin，HE)染色观察肝组织病理形态，通过Western blot和RT-PCR探讨肝组织脂代谢相关信号通路改变。实验经中国医学科学院药物研究所实验动物管理和使用委员会的审查批准。在人肝肿瘤细胞HepG2和TNFα诱导3T3-L1胰岛素抵抗脂肪细胞模型，通过Western blot探讨SZZ15-11对胰岛素信号通路和脂联素表达的影响。结果显示，SZZ15-11不仅可降低KKAy小鼠的高血糖、高血脂，增强胰岛素敏感性，还可增加小鼠空腹血胰高血糖素水平，促进糖负荷后胰岛素分泌;能改善小鼠肝组织脂肪变性，保护肝功能;在肝组织中，可上调AMPKα磷酸化，使胆固醇代谢相关基因Abcg8表达增加;在肝细胞和胰岛素抵抗脂肪细胞模型，可增强胰岛素信号，明显减弱TNFα对脂联素表达的抑制作用。提示GPR40激动剂SZZ15-11能有效调控糖脂代谢紊乱，是一新型的、有潜力的抗糖尿病候选化合物。

外文标题：GPR40 novel agonist SZZ15-11 regulates glucolipid metabolic disorders in spontaneous type 2 diabetic KKAy mice

外文摘要：G protein-coupled receptor(GPR)40,as one of GPRs family,plays a potential role in regulating glucose and lipid metabolism.To study the effect of GPR40 novel agonist SZZ15-11 on hyperglycemia and hyperlipidemia and its potential mechanism,spontaneous type 2 diabetic KKAy mice,human hepatocellular carcinoma HepG2 cells and murine mature adipocyte 3T3-L1 cells were used.KKAy mice were divided into four groups,vehicle group,TAK group,SZZ(50 mg·kg-1)group and SZZ(100 mg·kg-1)group,with oral gavage of 0.5％sodium carboxymethylcellulose(CMC),50 mg·kg-1 TAK875,50 and 100 mg·kg-1 SZZ15-11 respectively for 45 days.Fasting blood glucose,blood triglyceride(TG)and total cholesterol(TC),non-fasting blood glucose were tested.Oral glucose tolerance test and insulin tolerance test were executed.Blood insulin and glucagon were measured via enzyme-linked immunosorbent assay(ELISA).After mice's execution,liver tissue was harvested to test TG and TC content.Then pathological morphology of liver was observed through hematoxylin-eosin(HE)staining,and the lipid metabolism relative signal pathway was analyzed by Western blot and RT-PCR.The experiments were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College.At the same time,Akt phosphorylation level in HepG2 cells and adiponectin in 3T3-L1 cells treated with TNFα were measured with Western blot.The results show that SZZ 15-11 not only decreased blood glucose and lipid,improved insulin sensitivity,but also increased fasting blood glucagon and promoted insulin secretion after glucose loading in KKAy mice.Additionally,SZZ15-11 alleviated hepatic steatosis and liver dysfunction in KKAy mice.In liver tissue,SZZ15-11 increased AMPKα phosphorylation level and cholesterol metabolism relative gene Abcg8 transcription.In HepG2 cells,SZZ15-11 increased Akt phosphorylation level.In adipocyte 3T3-L1,SZZ15-11 recovered the decreased adiponectin expression by TNFα.This study proved that GPR40 agonist SZZ 15-11 could be a candidate compound for regulating glucolipid metabolic disorder.

外文关键词：

G protein-coupled receptor 40type 2 diabetesglucose and lipid metabolismhepatic steatosisinsulin resistance

作者：

雷蕾、翟佳羽、周甜、刘泉、刘率男、李彩娜、曹慧、冯存玉、吴敏、陈蕾蕾、雷丽冉、潘璇、刘站柱、环奕、申竹芳

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作者单位：

中国医学科学院、北京协和医学院药物研究所,天然活性物质与功能国家重点实验室,晶型药物研究北京市重点实验室,中国医学科学院糖尿病研究中心,北京 100050

郑州大学附属儿童医院药学部,河南郑州 450018

关键词：

G蛋白偶联受体40 2型糖尿病糖脂代谢肝脂肪变性胰岛素抵抗

基金：

国家自然科学基金资助项目国家自然科学基金资助项目国家自然科学基金资助项目中国医学科学院创新工程项目中国医学科学院创新工程项目河南省医学科技攻关计划项目

项目编号：

8180359782200883823739222022-I2M-2-0022021-I2M-1-026222102310496

出版年：

2024

DOI：

10.16438/j.0513-4870.2024-0410

药学学报

中国药学会中国医学科学院药物研究所

药学学报

CSTPCD北大核心

影响因子：1.274

ISSN：0513-4870

年,卷(期)：2024.59(10)